The present invention relates to novel polycyclic compounds having anti-tumor activity, pharmaceutical composition containing these compounds, the use of these compounds in the medical therapy as well as a process for the preparation of these compounds.
Indeno[2,1-c]quinolin-7-one derivatives having a substituted aminoalkylamino radical as a side chain are known to have anti-tumor activity. For example, 6-(2-dimethylamino-ethylamino)-3-hydroxy-7H-indeno[2,1-c]quinolin-7-one and its derivatives have been disclosed to have anti-tumor activity. See, EP 0713870 (1996). However, anti-tumor activity in this reference may not be sufficient for the treatment of tumor and thus, more potent anti-tumor compounds are desirable.
It is therefore advantageous in the art to provide more potent anti-tumor compounds for treatment of tumor.
The present invention is directed to novel polycyclic compounds of the formula [I], 
wherein;
ring A is a nitrogen-containing 5 or 6 membered heteroaromatic ring which may be substituted by R1 and R2;
R1 and R2 are independently hydrogen, halogen, (C1-C5) alkyl, hydroxy, mercapto, (C1-C5) alkoxy, (C4-C7) cycloalkyloxy, (C3-C7)cycloalkyl(C1-C5)alkyloxy, (C1-C5) alkylthio, (C1-C5) alkylsulfinyl, (C1-C5) alkylsulfonyl, amino, mono-(C1-C5)-alkylamino, di-(C1-C5)-alkylamino or xe2x80x94Yxe2x80x2xe2x80x94Zxe2x80x2xe2x80x94N(R6xe2x80x2)(R7xe2x80x2);
wherein
Yxe2x80x2 is O, S or N(R9xe2x80x2), wherein R9xe2x80x2 is hydrogen or (C1C5) alkyl; or when Yxe2x80x2 is N(R9xe2x80x2), N(R9xe2x80x2) forms an aliphatic ring together with N(R6xe2x80x2) and Zxe2x80x2;
Zxe2x80x2 is (C2-C5) alkylene; or Zxe2x80x2 forms an aliphatic ring together with N(R6xe2x80x2) and (NR9xe2x80x2); or Zxe2x80x2 forms an aliphatic ring together with N(R6xe2x80x2);
R6xe2x80x2 and R7xe2x80x2 are independently hydrogen, (C1-C5) alkyl, (C3-C5) alkenyl, (C4-C7) cycloalkyl, (C3-C7)cycloalkyl(C1-C5)alkyloxy or aryl(C1-C5)alkyl optionally substituted with one to three substituents selected from the group consisting of hydroxy, (C1-C5) alkoxy, amino, mono-(C1-C5)-alkylamino and di-(C1-C5)-alkylamino radical(s); or R6xe2x80x2 and R7xe2x80x2 form an aliphatic ring optionally containing one to three heteroatom(s) selected from oxygen, nitrogen and sulfur together with the adjacent nitrogen; or R6xe2x80x2 forms an aliphatic ring together with the adjacent nitrogen and Zxe2x80x2; or R6xe2x80x2 forms an aliphatic ring together with the adjacent nitrogen, N(R9xe2x80x2) and Zxe2x80x2;
ring B is a benzene ring, naphthalene ring or benzene ring substituted with (C1-C5) alkylenedioxy group which is optionally substituted by R3, R4 and R5;
R3, R4 and R5 are independently hydrogen, halogen, hydroxy, mercapto, (C1-C5) alkyl, (C1-C5) halogeno-alkyl, (C1-C5) alkoxy, (C1-C5) halogeno-alkoxy, (C3-C5) alkenyloxy, (C4-C7) cycloalkyloxy, (C3-C7)cycloalkyl(C1-C5)alkyloxy, aryl(C1-C5)alkyloxy, (C1-C5) alkylthio, (C1-C5) alkylsulfinyl, (C1-C5) alkylsulfonyl, amino, mono-(C1-C5)-alkylamino or di-(C1-C5)-alkylamino;
X is O or Nxe2x80x94Oxe2x80x94R8 wherein R8 is a hydrogen, (C1-C5) alkyl, (C3-C5) alkenyl, (C4-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C5)alkyloxy, aryl, or aryl(C1-C5)alkyl;
Y is O, S or N(R9) wherein R9 is hydrogen or (C1-C5) alkyl; or when Y is N(R9), N(R9) forms an aliphatic ring together with N(R6) and Z;
Z is (C2-C5) alkylene optionally substituted with (C1-C5) alkyl radical(s); or Z forms an aliphatic ring together with N(R6) and N(R9); or Z forms an aliphatic ring together with N(R6);
and
R6 and R7 are independently hydrogen, (C1-C5) alkyl, (C3-C5) alkenyl, (C4-C7) cycloalkyl, (C3-C7)cycloalkyl(C1-C5)alkyloxy or aryl(C1-C5)alkyl optionally substituted with hydroxy, (C1-C5) alkoxy, amino, mono-(C1-C5)-alkylamino or di-(C1-C5)-alkylamino radical(s); or R6 and R7 form an aliphatic ring optionally containing one to three heteroatom(s) selected from oxygen, nitrogen and sulfur together with the adjacent nitrogen; or R6 forms an aliphatic ring together with the adjacent nitrogen and Z; or R6 forms an aliphatic ring together with the adjacent nitrogen, N(R9) and Z,
as well as pharmaceutically acceptable salts thereof.
This invention is also directed to a pharmaceutical composition containing the above-described compounds, and a method for treating a cell proliferative disorder, especially in treatment of tumor, comprising administering to a patient in need thereof a therapeutically effective amount of the above-described compounds.
This invention is also directed to providing a process for the preparation of those compounds.
Unless otherwise indicated, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the present invention herein.
In this specification, the term xe2x80x9cnitrogen-containing 5 or 6 membered heteroaromatic ringxe2x80x9d is used to mean a radical of a 5 to 6 membered aromatic ring which contains at least one nitrogen atom and may further contain one or more heteroatom(s) selected from N, S and O. Preferably, xe2x80x9cnitrogen-containing 5 or 6 membered heteroaromatic ringxe2x80x9d means pyridine, pyrazine, pyridazine, pyrimidine, oxazole, thiazole, isoxazole, isothiazole, imidazole, pyrrole, triazole and the like, and more preferably, pyridine.
The term xe2x80x9calkylxe2x80x9d as used herein, alone or in combination, means a straight-chain or branched-chain hydrocarbon group containing a maximum of 12, preferably a maximum of 5, carbon atoms, e.g., methyl, ethyl, n-propyl, 2-methylpropyl (iso-butyl), 1-methylethyl (iso-propyl), n-butyl, and 1,1-dimethylethyl (t-butyl), and more preferably a maximum of 4 carbon atoms. The alkyl group may be unsubstituted or may be substituted with one or more substituents, preferably with one to three substituents, and most preferably with one substituent. The substituents are selected from the group consisting of hydroxy, alkoxy, amino, mono- or di-alkylamino, acetoxy, alkylcarbonyloxy, alkoxycarbonyl, carbamoyl and halogen.
The term xe2x80x9calkenylxe2x80x9d as used therein, alone or in combination, refers to a hydrocarbon chain as defined for alkyl having at least one olefinic double bond (including for example, allyl and butenyl) and having the general formula CmH2mxe2x88x921 wherein m is an integer greater than 2, preferably m is an integer of 3 to 7, and more preferably 3 to 5.
The term xe2x80x9calkylenexe2x80x9d refers to a biradical branched or unbranched hydrocarbon chain containing 1 to 5 carbon atoms, such as methylene (xe2x80x94CH2xe2x80x94), ethylene, propylene, trimethylene and tetramethylene. The alkylene group may be unsubstituted or may be substituted with one or more substituents, preferably with one to three substituents, and most preferably with one substituent. The substituents are selected from the group consisting of hydroxy, alkoxy, amino, mono- or di-alkylamino, acetoxy, alkylcarbonyloxy, alkoxycarbonyl, carbamoyl and halogen.
The term xe2x80x9carylxe2x80x9d refers to an aromatic carbocyclic radical, i.e., a 6 or 10 membered aromatic or partially aromatic ring, e.g., phenyl (xe2x80x9cPhxe2x80x9d), naphthyl or tetrahydronaphthyl, preferably phenyl or naphthyl, and most preferably phenyl. The aryl moiety is optionally substituted with one or more subsituents, preferably with one to three, most preferably one, selected from the group consisting of halogen, preferably fluorine, chlorine, alkoxycarbonyl (e.g., methoxycarbonyl), alkylcarbonyloxy (e.g., acetoxy), cyano, alkyl, alkoxy, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy, alkylthio, hydroxy, alkylcarbonylamino, heterocyclyl, sulfamoyl (i.e., H2NSO2xe2x80x94), amino, 1,3-dioxolyl and 1,4-dioxolyl. Especially preferred substituents are alkyl, alkoxy, hydroxy, halogen, amino, alkylamino, dialkylamino, alkylthio, sulfamoyl, benzyl or heterocyclyl.
The term xe2x80x9caryl(C1-C5)alkylxe2x80x9d refers to an alkyl group as defined above substituted with an aryl as defined above. The aryl group of the aryl(C1-C5)alkyl maybe substituted with one or more substituents, preferably one to three, most preferably with one substituent selected from the group consisting of halogen, preferably fluorine, chlorine, alkoxycarbonyl (e.g., methoxycarbonyl), alkylcarbonyloxy (e.g., acetoxy), cyano, alkyl, alkoxy, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy, alkylthio, hydroxy, alkylcarbonylamino, heterocyclyl, sulfamoyl, amino, 1,3-dioxolyl and 1,4-dioxolyl. Especially preferred substituents of aryl(C1-C5)alkyl are alkoxy, hydroxy, halogen, amino, mono- or di-alkylamino or alkylthio.
The term xe2x80x9calkoxyxe2x80x9d refers to the group xe2x80x94Oxe2x80x94Rxe2x80x2 wherein Rxe2x80x2 is an alkyl as defined above.
The term xe2x80x9ccycloalkylxe2x80x9d refers to a saturated, cyclic hydrocarbon group with 3-7 carbon atoms, preferably with 4-7 carbon atoms, more preferably 4-6 carbon atoms, i.e., cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl and the like. The cycloalkyl group may be substituted or unsubstituted. The substituents are selected from alkyl, phenyl, amino, hydroxy and halogen.
The term xe2x80x9ccycloalkyl alkylxe2x80x9d refers to a branched or straight chain monovalent saturated aliphatic carbon radical of 1 to 5, preferably 1 to 3 carbon atom(s) having a monovalent carbocyclic radical of 3 to 7 carbon atoms, preferably 3 to 6 carbon atoms.
The term xe2x80x9caliphatic ringxe2x80x9d refers to a monovalent carbocyclic radical of 3 to 7 carbon atoms, preferably 3 to 6 carbon atoms, such as cyclopropane, cyclobutane, cyclopentane and cyclohexane, which may contain 1 to 3 heteroatom(s), preferably 1 to 2, selected from oxygen, nitrogen and sulfur. The examples of aliphatic ring containing heteroatom(s) are morpholine ring, thiomorpholine ring, pyrrolidine ring, piperidine ring and piperazine ring.
The term xe2x80x9calkylthioxe2x80x9d refers to the group Rbxe2x80x94Sxe2x80x94, wherein Rb is an alkyl group as defined above.
The term xe2x80x9caminoxe2x80x9d refers to the group xe2x80x94NH2 and includes amino groups which are protected by a group known in the art such as a benzyloxycarbonyl group, acetyl group, alkoxycarbonyl group or benzyl group and the like.
The term xe2x80x9chalogenxe2x80x9d refers to fluoro, chloro, bromo and iodo.
The term xe2x80x9cheteroatomxe2x80x9d refers to oxygen, nitrogen and sulfur.
The term xe2x80x9chydroxyxe2x80x9d refers to the group xe2x80x94OH.
The term xe2x80x9ccyanoxe2x80x9d refers to the group xe2x80x94CN.
The term xe2x80x9cmercaptoxe2x80x9d refers to the group xe2x80x94SH.
The term xe2x80x9ccycloalkyl alkyloxyxe2x80x9d means the group Rcxe2x80x94Oxe2x80x94, wherein Rc is an cycloalkyl alkyl group as defined above.
The term xe2x80x9calkylsulfinylxe2x80x9d means the group Rdxe2x80x94SOxe2x80x94, wherein Rd is an alkyl group as defined above.
The term xe2x80x9calkylsulfonylxe2x80x9d means the group Rexe2x80x94SO2xe2x80x94, wherein Re is an alkyl group as defined above.
The term xe2x80x9chalogeno alkylxe2x80x9d means alkyl substituted with one or more halogen atoms.
The term xe2x80x9calkenyloxyxe2x80x9d means the group Rfxe2x80x94Oxe2x80x94, wherein Rf is an alkenyl group as defined above.
The term xe2x80x9ccycloalkyloxyxe2x80x9d means the group Rgxe2x80x94Oxe2x80x94, wherein Rg is a cycloalkyl group as defined above.
The term xe2x80x9cmono- and di-alkylaminoxe2x80x9d refers to an amino group substituted with an alkyl group or a di-alkyl group as defined above, i.e., alkyl-NHxe2x80x94 and dialkyl-Nxe2x80x94.
The term xe2x80x9cbenzene ring having (C1-C5) alkylenedioxy groupxe2x80x9d preferably means benzo[1,3]dioxole and 2,3-dihydrobenzo[1,4]dioxine and most preferably benzo[1,3]dioxole.
In the present invention, the expression xe2x80x9coptionally substituted withxe2x80x9d means that substitution can occur at one or more positions, preferably at one to three positions, and, unless otherwise indicated, that the substituents are independently selected from the specified options.
xe2x80x9cPharmaceutically acceptable saltxe2x80x9d refers to conventional acid-addition salts or base-addition salts which retain the biological effectiveness and properties of the compounds of formula [I], and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Sample acid-addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like. Sample base-addition salts include those derived from potassium, sodium, ammonium, and quarternary ammonium hydroxide, such as, for example, tetramethylammonium hydroxide. The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d also comprises prodrugs of polycyclic compounds of formula [I] or corresponding salts thereof.
xe2x80x9cPharmaceutically acceptable,xe2x80x9d such as pharmaceutically acceptable carrier, excipient, prodrug, etc., means pharmacologically acceptable and substantially non-toxic to the subject to which the particular compound is administered.
xe2x80x9cPharmaceutically active metabolitexe2x80x9d means a metabolic product of a compound of formula [I] which is pharmaceutically acceptable and effective.
The term xe2x80x9cprodrugxe2x80x9d refers to the compounds of the formula [I] that may be converted under physiological conditions or by solvolysis to any of the compounds of the formula [I] or to a pharmaceutically acceptable salts of the compounds of the formula [I]. A prodrug may be inactive when administered to a subject but is converted in vivo to an active compound of the formula [I].
In a preferred embodiment, the invention comprises compounds of formula [I] wherein ring A is a nitrogen-containing 5 or 6 membered heteroaromatic ring, which may be substituted by R1 and R2. Preferably, ring A is a pyridine, pyrazine, pyridazine or pyrimidine ring, and more preferably a pyridine ring.
In a preferred embodiment, ring B is a benzene ring, naphthalene ring or benzene ring having (C1-C5) alkylenedioxy group which is optionally substituted by R3, R4 and R5.
In a further preferred embodiment, the invention comprises compounds of formula [I], wherein ring B is a benzene ring, naphthalene ring or benzene ring having (C1-C5) alkylenedioxy group. More preferably, ring B is a benzene ring or benzo[1,3]dioxole. Most preferably, ring B is a benzene ring.
In a preferred embodiment, the invention comprises compounds of formula [I] wherein one of R1 and R2 is hydrogen, (C1-C5) alkyl or xe2x80x94NHCH2C(CH3)2CH2N(CH3)2. More preferably, one of R1 and R2 is hydrogen, xe2x80x94CH3 or xe2x80x94NHCH2C(CH3)2CH2N(CH3)2.
In another preferred embodiment, the present invention comprises compounds of formula [I], wherein R1 is hydrogen and R2 is xe2x80x94CH3.
In another preferred embodiment, the present invention comprises compounds of formula [I], wherein R1 and R2 are hydrogen.
In a further preferred embodiment, the invention comprises compounds of formula [I], wherein X is O, Nxe2x80x94OH or Nxe2x80x94OCH3.
In a further preferred embodiment, the invention comprises compounds of formula [I], wherein xe2x80x94Yxe2x80x94Zxe2x80x94N(R6)(R7) is xe2x80x94NHxe2x80x94CH2CH2xe2x80x94N(CH3)2 or xe2x80x94NHxe2x80x94CH2CH2-(pyrrolidin-1-yl).
In a preferred embodiment, the present invention comprises compounds of formula [I] wherein R3, R4 and R5 are hydrogen, one is fluoro and the two others are hydrogen, one is hydroxy and the two others are hydrogen, one is OCH3 and the two others are hydrogen, or one is hydrogen, one is hydroxy and the third is CH3.
Most preferably, the present invention comprises polycyclic compounds of formula [I] wherein R3, R4 and R5 are hydrogen; R3, R4 are hydrogen and R5 is hydroxy; R3, R4 are hydrogen and R5 is OCH3; or R3 is hydrogen, R4 is methyl and R5 is hydroxy.
Preferred polycyclic compounds in accordance with the present invention are as follows:
a) 6-(2-dimethylamino-ethylamino)-3-methoxy-5,9-diaza-benzo[c]fluoren-7-one,
b) 6-(2-dimethylamino-ethylamino)-3-hydroxy-5,9-diaza-benzo[c]fluoren-7-one,
c) 6-(2-dimethylamino-ethylamino)-5,9-diaza-benzo[c]fluoren-7-one,
d) 6-(2-dimethylamino-ethylamino)-2-fluoro-3-methoxy-5,9-diaza-benzo[c]fluoren-7-one,
e) 6-(2-dimethylamino-ethylamino)-3-hydroxy-4-methyl-5,9-diaza-benzo[c]fluoren-7-one,
f) 6-(2-dimethylamino-ethylamino)-3-ethoxy-5,9-diaza-benzo[c]fluoren-7-one,
g) 3-allyloxy-6-(2-dimethylamino-ethylamino)-5,9-diaza-benzo[c]fluoren-7-one,
h) 3-chloro-6-(2-dimethylamino-ethylamino)-5,9-diaza-benzo[c]fluoren-7-one,
i) 6-(2-dimethylamino-ethylamino)-1,3-dimethoxy-5,9-diaza-benzo[c]fluoren-7-one,
j) 6-(2-dimethylamino-ethylamino)-5,9-diaza-indeno[1,2-a]phenanthren-7-one,
k) 6-(2-dimethylamino-ethylamino)-1,3-dioxa-5,9-diaza-indeno[5,6-c]fluoren-7-one,
l) 6-(2-dimethylamino-ethylamino)-3-methoxy-5,10-diaza-benzo[c]fluoren-7-one,
m) 6-(2-dimethylamino-ethylamino)-3-hydroxy-5,10-diaza-benzo[c]fluoren-7-one,
n) 3-hydroxy-6-(2-pyrrolidin-1-yl-ethylamino)-5,10-diaza-benzo[c]fluoren-7-one,
o) 6-(2-dimethylamino-ethylamino)-3-hydroxy-4-methyl-5,10-diaza-benzo[c]fluoren-7-one,
p) 3-methoxy-4-methyl-6-(2-pyrrolidin-1-yl-ethylamino)-5,10-diaza-benzo[c]fluoren-7-one,
q) 3-hydroxy-4-methyl-6-(2-pyrrolidin-1-yl-ethylamino)-5,10-diaza-benzo[c]fluoren-7-one,
r) 3-methoxy-6-(2-pyrrolidin-1-yl-ethylamino)-5,9-diaza-benzo[c]fluoren-7-one,
s) 3-methoxy-6-(2-methylamino-ethylamino)-5,9-diaza-benzo[c]fluoren-7-one,
t) 3-methoxy-6-(4-methyl-piperazin-1-yl)-5,9-diaza-benzo[c]fluoren-7-one,
u) 3-hydroxy-6-(2-pyrrolidin-1-yl-ethylamino)-5,9-diaza-benzo[c]fluoren-7-one,
v) 3-hydroxy-6-(2-morpholin-4-yl-ethylamino)-5,9-diaza-benzo[c]fluoren-7-one,
w) 6-[(2-dimethylamino-ethyl)-methyl-amino]-3-hydroxy-5,9-diaza-benzo[c]fluoren-7-one,
x) 6-(2-dimethylamino-ethoxy)-3-hydroxy-5,9-diaza-benzo[c]fluoren-7-one,
y) 6-(2-dimethylamino-ethylamino)-3-methoxy-9-methyl-5,10-diaza-benzo[c]fluoren-7-one,
z) 6,11-bis-(2-dimethylamino-ethylamino)-3-methoxy-5,10-diaza-benzo[c]fluoren-7-one,
aa) 11-(3-dimethylamino-2,2-dimethyl-propylamino)-6-(2-dimethylamino-ethylamino)-3-methoxy-5,10-diaza-benzo[c]fluoren-7-one,
bb) 11-(3-dimethylamino-2,2-dimethyl-propylamino)-6-(2-dimethylamino-ethylamino)-3-methoxy-4-methyl-5,10-diaza-benzo[c]fluoren-7-one,
cc) 6-(2-dimethylamino-ethylamino)-3-hydroxy-9-methyl-5,10-diaza-benzo[c]fluoren-7-one,
dd) 6-(2-dimethylamino-ethylamino)-3-hydroxy-8-methyl-5,9-diaza-benzo[c]fluoren-7-one,
ee) 11-(3-dimethylamino-2,2-dimethyl-propylamino)-6-(2-dimethylamino-ethylamino)-3-hydroxy-4-methyl-5,10-diaza-benzo[c]fluoren-7-one,
ff) 6-(2-dimethylamino-ethylamino)-3-hydroxy-5,9-diaza-benzo[c]fluoren-7-one oxime,
gg) 6-(2-dimethylamino-ethylamino)-3-hydroxy-5,9-diaza-benzo[c]fluoren-7-one O-methyl-oxime and
hh) 6-(2-dimethylamino-ethylamino)-3-hydroxy-4-methyl-5,9-diaza-benzo[c]fluoren-7-one O-methyl-oxime.
Further preferred polycyclic compounds in accordance with the present invention are as follows:
a) 6-(2-dimethylamino-ethylamino)-3-methoxy-5,9-diaza-benzo[c]fluoren-7-one,
b) 6-(2-dimethylamino-ethylamino)-3-hydroxy-5,9-diaza-benzo[c]fluoren-7-one,
c) 6-(2-dimethylamino-ethylamino)-5,9-diaza-benzo[c]fluoren-7-one,
d) 6-(2-dimethylamino-ethylamino)-3-hydroxy-5,10-diaza-benzo[c]fluoren-7-one,
e) 3-hydroxy-6-(2-pyrrolidin-1-yl-ethylamino)-5,10-diaza-benzo[c]fluoren-7-one,
f) 6-(2-dimethylamino-ethylamino)-3-hydroxy-4-methyl-5,10-diaza-benzo[c]fluoren-7-one,
g) 3-hydroxy-4-methyl-6-(2-pyrrolidin-1-yl-ethylamino)-5,10-diaza-benzo[c]fluoren-7-one,
h) 3-hydroxy-6-(2-pyrrolidin-1-yl-ethylamino)-5,9-diaza-benzo[c]fluoren-7-one,
i) 6-(2-dimethylamino-ethylamino)-3-hydroxy-9-methyl-5,10-diaza-benzo[c]fluoren-7-one, and
j) 11-(3-dimethylamino-2,2-dimethyl-propylamino)-6-(2-dimethylamino-ethylamino)-3-hydroxy-4-methyl-5,10-diaza-benzo[c]fluoren-7-one.
Polycyclic compounds of the formula [I] of the present invention can be produced via following methods:
A process for producing polycyclic compounds of the formula [I], 
wherein ring A, ring B, R1, R2, R3, R4, R5, R6, R7, Y and Z, are the same as defined above X is O,
which comprises substitution of -Hal of a compound of the formula [VI] or xe2x80x94OS(O2)R12 of a compound of the formula [VII] by xe2x80x94Yxe2x80x94Zxe2x80x94N(R6)(R7), 
wherein ring A, ring B, R1, R2, R3, R4 and R5 are the same as defined above; Hal is halogen; and R12 is (C1-C5) alkyl, (C1-C5) halogenoalkyl or aryl,
effected by reacting a compound of the formula [VI] or [VII] with a compound of the formula [VIII], 
wherein R6, R7, Y and Z are the same as defined above.
In more detail, the compounds of the present invention can be prepared as follows:
Process 1
Key intermediates, compounds 6 and 7, can be prepared according to the following Flow Chart 1:
Flow Chart 1: Preparation of key intermediates. 
The definitions of the symbols in Flow Chart 1 are as follows. Hal is halogen. R11 is (C1-C5) alkyl such as methyl, ethyl, propyl and butyl. R1a and R2a are R1 and R2, respectively, or protected R1 and protected R2 which can be converted to R1 and R2, respectively, by methods known in the art. R12 is (C1-C5) alkyl such as methyl, (C1-C5) halogenoalkyl such as trifluoromethyl or aryl, such as p-methylphenyl and phenyl. R3a, R4a and R5a are the same as R3, R4 and R5 defined above, respectively; or protected R3, protected R4 and protected R5 which can be easily converted to R3, R4 and R5, respectively, by known methods per se. ArNH2 is an aniline derivative which is optionally substituted by R3a, R4a and R5a. The definitions of ring A and ring B are the same as defined above.
For example, typically, dicarboxylic acid 1 is converted into compound 3 by 1) refluxing compound 1 in acetic anhydride and then 2) treating the resulting acid anhydride with acetoacetic acid ester in the presence of a base such as triethylamine in acetic anhydride at room temperature (see, Robin D. Allan and Joyce Fong, Aust. J. Chem., Vol. 36, Pp. 1221-1226, 1983). Compound 3 can also be prepared from dicarboxylic acid anhydride 2 by treatment with acetoacetic acid ester and a base such as triethylamine in acetic anhydride at room temperature (see, Binder D., Monatshefte fur Chemie, Vol. 105, Pp. 179-186, 1974). Compound 4 is obtained by heating compound 3 with ArNH2 in an inert solvent such as toluene. The reaction temperature is from 40xc2x0 C. to 160xc2x0 C., preferably 80xc2x0 C. to 110xc2x0 C. The amide 4 can be cyclized to obtain polycyclic lactam 5 by heating compound 4 in an acid such as polyphosphoric acid, trifluoromethane sulfonic acid and sulfonic acid. The compound 5 can be halogenated by a halogenating reagent such as thionyl chloride, thionyl bromide, phosphorous oxy-chloride, phosphorous chloride and phosphorous bromide. The preferable temperature for this reaction ranges from room temperature to reflux, and most preferably 50xc2x0 C. to 110xc2x0 C. Thus, the key intermediate 6 can be synthesized. The compound 5 can be sulfonylated by treating 5 with a sulfonylating agent such as methanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride and trifluoromethanesulfonic anhydride. Typically, compound 5, the sulfonylating agent and a phase transfer catalyst such as tetrabutylammonium bromide are suspended in a mixture of an organic solvent, such as dichloromethane and water containing a base such as sodium hydroxide, and the mixture is vigorously stirred for a few hours to a few days, typically overnight.
When one of R1a, R2a, R3a, R4a and R5a of compound 6 is alkoxy such as methoxy. This alkoxy group can be cleaved by sulfuric acid at 160xc2x0 C. to give a hydroxy derivative. The resulting phenol group can be further modified by methods known in the art. For example, when the phenol having the general formula 6 is treated with (C1-C5) alkyl halide, aryl(C1-C5)alkyl halide, (C3-C5) alkenyl halide, (C4-C7) cycloalkyl halide and (C3-C7) cycloalkyl (C1-C5) alkyl halide, (C1-C5) alkoxy, aryl (C1-C5)alkyloxy, (C3-C5)alkenyloxy, (C4-C7)cycloalkyloxy and C3-C7)cycloalkyl(C1-C5) alkyloxy derivatives can be prepared, respectively.
Active polycyclic compounds can be synthesized from the key intermediates 6 or 7 by reacting 6 or 7 with HYxe2x80x94Zxe2x80x94N(R6a)(R7a) (various amines, alcohols and thiols) as shown in Flow Chart 2. The definitions of Y and Z are the same as defined above and R6a and R7a are defined as below.
Process 2
Flow Chart 2: Modification of key intermediates. 
The definitions of the symbols in Flow Chart 2 are as follows. Hal is halogen. R12 is (C1-C5) alkyl such as methyl, (C1-C5) halogenoalkyl such as trifluoromethyl or aryl such as p-methylphenyl and phenyl. R3a, R4a and R5a are the same as R3, R4 and R5 defined above, respectively; or protected R3, protected R4 and protected R5 which can be easily converted to R3, R4 and R5, respectively, by methods known to the skilled artisan. R6a and R7a are the same as R6 and R7 defined above, respectively; or protected R6 and protected R7 which can be easily converted to R6 and R7, respectively, by methods known in the art. The definitions of ring A, ring B, Y and Z are the same as defined above.
When Y is N(R9) wherein R9 has the same meaning defined above, the key intermediates 6 and 7 can be aminated by treatment of 6 or 7 with an amine, HN(R9)xe2x80x94Zxe2x80x94N(R6a)(R7a), in a solvent such as pyridine and N,N-dimethylformamide (DMF) or without solvent. The reaction temperature for this step is preferably 0xc2x0 C. to 115xc2x0 C., and most preferably room temperature to 100xc2x0 C.
When Y is O or S, the key intermediates 6 and 7 can be reacted with 6 or 7 with HYxe2x80x94Zxe2x80x94N(R6a)(R7a) in the presence of a base such as NaH in a solvent such as DMF. The reaction temperature for this step is preferably xe2x88x9220xc2x0 C. to 50xc2x0 C., and most preferably 0xc2x0 C. to room temperature.
The active polycyclic compounds obtained can be further modified by the methods as shown in Flow Chart 3 and Flow Chart 4.
Process 3
Flow Chart 3: Further modification of ring A. 
The definitions of the symbols in Flow Chart 3 are as follows. Compound 8xe2x80x2 is the same as compound 8 in Flow Chart 2 wherein R1a is halogen. Hal is halogen. R1b is a hydroxy, (C1-C5) alkoxy, amino, mono-(C1-C5)-alkyl-amino, di-(C1-C5)-alkyl-amino or xe2x80x94Yxe2x80x2xe2x80x94Zxe2x80x2xe2x80x94N(R6axe2x80x2)(R7axe2x80x2) radical wherein Yxe2x80x2 and Zxe2x80x2 have the same definitions as described above; R6axe2x80x2 and R7axe2x80x2 are the same as R6xe2x80x2 and R7xe2x80x2, respectively, or protected R6xe2x80x2 and protected R7xe2x80x2 which can be converted to R6xe2x80x2 and R7xe2x80x2, respectively, by methods known in the art. R2a, R3a, R4a and R5a are the same as R2, R3, R4 and R5, respectively, or protected R2, protected R3, protected R4 and protected R5 which can be converted to R2, R3, R4 and R5, respectively, by methods known in the art. R6a and R7a are the same as R6 and R7, respectively, or protected R6 and protected R7 which can be converted to R6 and R7, respectively, by methods known in the art. Ring A, ring B, Y and Z have the same definitions as mentioned above.
When the alpha position of the ring nitrogen in the ring A is substituted by halogen such as Cl, this halogen can also be replaced by various substituents such as hydroxy, (C1-C5) alkoxy, amino, mono-(C1-C5)-alkylamine, di-(C1-C5)-alkylamine or xe2x80x94Yxe2x80x2xe2x80x94Zxe2x80x2xe2x80x94N(R6axe2x80x2)(R7axe2x80x2) as shown in Flow Chart 3 by practically the same method as the step G in Flow Chart 2.
Process 4
The cyclopentadiene moiety of the polycyclic compounds can be further modified by the method in Flow Chart 4.
Flow Chart 4: Modification of the cyclopentadiene ring. 
Ring A, ring B, R1, R2, R3, R4, R5, R6, R7, R8, Y and Z have the same definitions as defined above.
The ketone group of the cyclopentadiene moiety can be modified by the reaction with oxime or various oxime-ethers (H2Nxe2x80x94Oxe2x80x94R8) in the absence or in the presence of an acid such as hydrochloric acid, hydrobromic acid and acetic acid in an appropriate solvent such as pyridine at an elevated temperature, typically at about 80xc2x0 C.
Protective groups which may be used in processes 1 to 3 can typically be cleaved as follows: 1) when a phenol group is protected by methyl or benzyl ether, the protective group can be cleaved by BBr3 treatment or acid hydrolysis using hydrobromic acid or sulfuric acid to give a phenol group and 2) when an amino group is protected by t-butoxycarbonyl (Boc), the protective group can be cleaved by acid such as trifluoroacetic acid to give an amino group.
The manufacture of the pharmaceutically acceptable acid addition salts of the compound of the formula [I] can be carried out by treating a free base of the compound represented by the formula [I] with an acid in a procedure known in the art for the salt formation. Examples of therapeutically acceptable acids useful in the above process are inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid and sulfuric acid) and organic acids (e.g., oxalic acid, acetic acid, formic acid, trifluoroacetic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, citric acid, salicylic acid, sorbic acid, lactic acid and methanesulfonic acid). Moreover, the compounds of the formula [I] can be converted into hydrates or solvates, and their salts by various methods known to those skilled in the art.
The polycyclic compounds of the formula [I] show strong anti-tumor activity against various tumor cell lines. This anti-tumor activity indicates that the compounds of the formula [I] and pharmaceutically acceptable salts thereof can be anti-tumor agents.
The polycyclic compounds of the formula [I] and pharmaceutically acceptable salts thereof are very strong cytotoxic agents. They are active against a variety of cell lines including colon cancer cell lines, non-small cell lung cancer cell lines, pancreatic cancer cell lines and gastric cancer cell lines, etc.
Thus, the polycyclic compounds of the present invention are useful for the treatment of cancer. Accordingly, the present invention comprises the use of the above compounds for the manufacture of medicaments for the treatment of cancer and the corresponding pharmaceutical compositions, which comprise a polycyclic compound as defined above and a pharmaceutically acceptable carrier.
For example, they are useful in treating leukemia, lymphoma, myeloma, prostate cancer, breast cancer, hepatoma, glioblastoma, ovarian cancer, melanoma, lung cancer, colorectal cancer, pancreatic cancer, and gastric cancer and so on.
The anti-tumor activity of the polycyclic compounds of the present invention can be demonstrated as follows:
Determination of the Anti-tumor Activity
Anti-proliferative Activity Assay
A single suspension of tumor cells was inoculated to the serially diluted 96-well microtestplate. Then the testplate was incubated in the 5% CO2 ambience at 37xc2x0 C. for 4 days (2-3xc3x97103 cells/well). The degree of cell growth in a monolayer was measured by using WST-8 (Dojindo, Japan). IC50 values of the polycyclic compounds concerned against tumor cells were calculated as the concentration of drug yielding 50% OD of the control growth. The IC50 value measures the drug concentration for 50% inhibition of the growth of tumor cells in vitro as compared to the control.
The anti-tumor activity of polycyclic compounds of the formula [I] against in vitro growth of HCT116 cell line (colorectal cancer) is summarized in Table 1.
Reference compound has been disclosed in EP 0713870 (1996) as an anti-tumor agent.
The acute toxicity (LD50) of the polycycle compounds of the present invention was examined by intravenous administration in mice. The LD50 value of the compounds was more than 90 mg/Kg.
For clinical use, the polycycle compounds of the formula [I], their prodrugs, or salt forms thereof and the like can be administered alone, but will generally be administered in pharmaceutical admixture formulated as appropriate to the particular use and purpose desired, by mixing excipient, binding agent, lubricant, disintegrating agent, coating material, emulsifier, suspending agent, solvent, stabilizer, absorption enhancer and/or ointment base. The admixture can be used for oral, injectable, rectal or topical administration.
In more detail, as mentioned earlier, medicaments containing a compound of formula [I] or its prodrug are also a part of the present invention, as is a process for the manufacture of such medicaments, whose process comprises bringing one or more compounds of formula [I] and, if desired, one or more other therapeutically valuable substances into a galenical administration form.
The pharmaceutical compositions may be administered orally, for example in the form of tablets, coated tablets, dragxc3xa9es, hard or soft gelatine capsules, solutions, emulsions or suspensions. Administration can also be carried out rectally, for example using suppositories; locally or percutaneously, for example using ointments, creams, gels or solutions; or parenterally, for example using injectable solutions.
For the preparation of tablets, coated tablets, dragxc3xa9es or hard gelatine capsules, the compounds of the present invention may be admixed with pharmaceutically inert, inorganic or organic excipients. Examples of suitable excipients for tablets, dragxc3xa9es or hard gelatine capsules include lactose, maize starch or derivatives thereof, talc or stearic acid or salts thereof.
Suitable excipients for use with soft gelatine capsules include, for example, vegetable oils, waxes, fats, semi-solid or liquid polyols, etc. According to the nature of the active ingredients, it may however be the case that no excipient is needed at all for soft gelatine capsules.
For the preparation of solutions and syrups, excipients which may be used include for example water, polyols, saccharose, invert sugar and glucose.
For injectable solutions, excipients which may be used include for example water, alcohols, polyols, glycerine, and vegetable oils.
For suppositories, and local or percutaneous application, excipients which may be used include for example natural or hardened oils, waxes, fats and semi-solid or liquid polyols.
The pharmaceutical compositions may also contain preserving agents, solubilizing agents, stabilizing agents, wetting agents, emulsifiers, sweeteners, colorants, odorants, salts for the variation of osmotic pressure, buffers, coating agents or antioxidants. They may also contain other therapeutically valuable agents.
In summary, a pharmaceutical formulation for oral administration may be granule, tablet, sugar coated tablet, capsule, pill, suspension or emulsion, which for parenteral injection, for example, intravenously, intramuscularly or subcutaneously, may be used in the form of a sterile aqueous solution which may contain other substances, for example, salts or glucose to make the solution isotonic. The anti-tumor agent can also be administered in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder.
The daily dosage level of the polycyclic compounds of the formula [I] is from 5 to 2,000 mg/m2 when administered by either the oral or parenteral route. Thus, tablets or capsules can contain from 5 mg to 1,000 mg of active compound for administration singly or two or more at a time as appropriate. In any event, the actual dosage can be determined by the weight and response of the particular patient.
The following examples illustrate the preferred methods for the preparation of the compounds of the present invention, which are not intended to limit the scope of the invention thereto.